Oat1 - rat

Oat1 (organic anion transporter), rat

Aliases: Orctl1, Paht, Roat1

Gene name: Solute carrier organic anion transporter family 22 member 6

The classical organic anion transporter Oat1 was first cloned from the rat [1, 2], and this was followed by the identification of the human ortholog. rOat1, mainly expressed at the basolateral membrane of the renal proximal tubules, is responsible for the tubular uptake of organic anions from blood, such as p-aminohippurate (PAH), and also contributes to the excretion of salicylates and cephalosporins, among others [3-6]. rOat1 is also expressed at a lower level in the brain, preferentially in the cortex [2]. Nucleoside analog antiviral drugs without a phosphate group are also transported by rOat1. Zidovudine, acyclovir, adefovir, cidofovir, zalcitabine, didanosine, lamivudine, stavudine, and trifluridine were shown to be substrates of rOat1, whereas foscarnet, a phosphate analog, was not. Weak inhibition was observed with acyclovir, amantadine, AZT, ganciclovir, and others [7]. Anionic diuretics such as acetazolamide, bumetanide, furosemide, chlorothiazide, and hydrochlorothiazide were tested as possible interactors of rOat1. Low Ki values of furosemide and bumetanide indicated a high inhibitory potential of these drugs on rOat1 [5]. Interaction of rOat1 with NSAIDs was demonstrated using an oocyte expression system. PAH uptake mediated by rOat1 was inhibited by diclofenac, ibuprofen, ketoprofen, naproxen, and piroxicam [8]. Kynurenic acid, one of the final metabolites of tryptophan, is accepted as a uremic toxin [9], and increased kynurenic acid content in the brain has been linked to schizophrenia [10]. Whereas kynurenic acid is a good substrate of human organic anion transporters hOAT1 and hOAT3 [11], the transport activity of rOat1 on kynurenic acid was comparatively low [12]. Gaboxadol was also a substrate for the renal transporter rOat1 [13]. Sulfonylureas and nateglinide interfere with rOat1, but these drugs themselves are not translocated by the transporter [14]. The β-lactam antibiotic piperacillin was shown to inhibit rOat1/3, and through this action it potentiated the β-lactamase-blocking effect of its co-drug tazobactam, an Oat1/3 substrate [15]. Indirect inhibition of rOat1 activity was observed following the administration of D-malate, which exerted its effect by decreasing the renal content of α-ketoglutarate [16].

References

1.    Sekine, T., et al., Expression cloning and characterization of a novel multispecific organic anion transporter. J Biol Chem, 1997. 272(30): p. 18526-9.
2.    Sweet, D.H., N.A. Wolff, and J.B. Pritchard, Expression cloning and characterization of ROAT1. The basolateral organic anion transporter in rat kidney. J Biol Chem, 1997. 272(48): p. 30088-95.
3.    Uwai, Y., et al., Functional characterization of the rat multispecific organic anion transporter OAT1 mediating basolateral uptake of anionic drugs in the kidney. FEBS Lett, 1998. 438(3): p. 321-4.
4.    Tojo, A., et al., Immunohistochemical localization of multispecific renal organic anion transporter 1 in rat kidney. J Am Soc Nephrol, 1999. 10(3): p. 464-71.
5.    Uwai, Y., et al., Interaction and transport of thiazide diuretics, loop diuretics, and acetazolamide via rat renal organic anion transporter rOAT1. J Pharmacol Exp Ther, 2000. 295(1): p. 261-5.
6.    Uwai, Y., H. Saito, and K. Inui, Interaction between methotrexate and nonsteroidal anti-inflammatory drugs in organic anion transporter. Eur J Pharmacol, 2000. 409(1): p. 31-6.
7.    Wada, S., et al., Rat multispecific organic anion transporter 1 (rOAT1) transports zidovudine, acyclovir, and other antiviral nucleoside analogs. J Pharmacol Exp Ther, 2000. 294(3): p. 844-9.
8.    Apiwattanakul, N., et al., Transport properties of nonsteroidal anti-inflammatory drugs by organic anion transporter 1 expressed in Xenopus laevis oocytes. Mol Pharmacol, 1999. 55(5): p. 847-54.
9.    Vanholder, R., et al., Review on uremic toxins: classification, concentration, and interindividual variability. Kidney Int, 2003. 63(5): p. 1934-43.
10.    Nilsson, L.K., et al., Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophrenia. Schizophr Res, 2005. 80(2-3): p. 315-22.
11.    Uwai, Y., H. Honjo, and K. Iwamoto, Interaction and transport of kynurenic acid via human organic anion transporters hOAT1 and hOAT3. Pharmacol Res, 2012. 65(2): p. 254-60.
12.    Uwai, Y., H. Hara, and K. Iwamoto, Transport of Kynurenic Acid by Rat Organic Anion Transporters rOAT1 and rOAT3: Species Difference between Human and Rat in OAT1. Int J Tryptophan Res, 2013. 6: p. 1-6.
13.    Larsen, M., et al., 5-Hydroxy-L-tryptophan alters gaboxadol pharmacokinetics in rats: involvement of PAT1 and rOat1 in gaboxadol absorption and elimination. Eur J Pharm Sci, 2010. 39(1-3): p. 68-75.
14.    Uwai, Y., et al., Inhibitory effect of anti-diabetic agents on rat organic anion transporter rOAT1. Eur J Pharmacol, 2000. 398(2): p. 193-7.
15.    Yang, S., et al., Piperacillin enhances the inhibitory effect of tazobactam on beta-lactamase through inhibition of organic anion transporter 1/3 in rats. Asian J Pharm Sci, 2019. 14(6): p. 677-686.
16.    Uwai, Y., T. Kawasaki, and T. Nabekura, D-Malate decreases renal content of alpha-ketoglutarate, a driving force of organic anion transporters OAT1 and OAT3, resulting in inhibited tubular secretion of phenolsulfonphthalein, in rats. Biopharm Drug Dispos, 2017. 38(8): p. 479-485.